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EP0145450B1 - 6-(2-(4-(1H-Imidazol-1-yl)phenyl-alkylene oder alkenylene-3(2H)-Pyridazinone oder 4,5-Dihydropyridazinone und Verfahren zu deren Herstellung - Google Patents

6-(2-(4-(1H-Imidazol-1-yl)phenyl-alkylene oder alkenylene-3(2H)-Pyridazinone oder 4,5-Dihydropyridazinone und Verfahren zu deren Herstellung Download PDF

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Publication number
EP0145450B1
EP0145450B1 EP84308465A EP84308465A EP0145450B1 EP 0145450 B1 EP0145450 B1 EP 0145450B1 EP 84308465 A EP84308465 A EP 84308465A EP 84308465 A EP84308465 A EP 84308465A EP 0145450 B1 EP0145450 B1 EP 0145450B1
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EP
European Patent Office
Prior art keywords
compound
phenyl
dihydro
imidazol
formula
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Expired
Application number
EP84308465A
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English (en)
French (fr)
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EP0145450A2 (de
EP0145450A3 (en
Inventor
Ila Sircar
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Warner Lambert Co LLC
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Warner Lambert Co LLC
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Priority to AT84308465T priority Critical patent/ATE46336T1/de
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Publication of EP0145450A3 publication Critical patent/EP0145450A3/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings

Definitions

  • 6-Pyridyl-vinyl-pyridazine-3(2H)-one and the 4,5-dihydro compound have been described as having cardiotonic and/or antihypertensive activity in European Patent Application 81,906.
  • EP-0071060 discloses compounds of the following general formula: in which m is an integer of from 1 to 12.
  • EP-0075436 discloses, inter alia, compounds of the following general formula: in which A may be the radical: and in which R 2 and R 3 are hydrogen or lower alkyl, Y may be hydrogen, and R, R' and R 1 may be hydrogen, lower alkyl or hydroxy alkyl.
  • EP-0085227 relates to compounds of the following general formula: in which X is ⁇ CR 1 R 2 ⁇ , Y is -0-, ⁇ S ⁇ or -NR 3- , A may be an alkylene of 1 to 4 carbon atoms or alkenylene of 2 to 4 carbon atoms, and Het is a 5- or 6-membered heterocyclic ring which may include two nitrogen atoms, the ring optionally being substituted by one or two substituents.
  • the present invention relates to 4,5-dihydro-6-[2-[4-(1H-imidazol-1-yl)phenyl)alkylenyl and alkylene-3(2H)-pyridazinones and their derivative compounds which have valuable pharmacological properties and in particular cardiotonic, antihypertensive, and antithrombotic activities.
  • the present invention is a compound of the formula (I): wherein signifies a single or double bond; R 1 , R 2 , and R 3 are each independently hydrogen, lower C 1-4 alkyl, hydroxy lower C 1 - 4 alkyl or R 2 and R 3 when taken together may form a ring containing five to seven carbon atoms or a benzene ring; R 4 and R s are each independently hydrogen or lower C 1 - 4 alkyl; A is alkylene of one to four carbon atoms or alkylene of two to four carbon atoms, or a pharmaceutically acceptable acid addition salt thereof.
  • the present invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising an effective amount of a compound of formula I together with a pharmaceutically acceptable carrier, and to a process for preparing the compound of formula I.
  • the compounds of the present invention may be employed in a method for increasing cardiac contractility in a mammal in need thereof, which method comprises administering to said mammal an effective amount of a pharmaceutical composition containing a compound of formula I. They may also be employed in a method of lowering blood pressure in a mammal suffering from hypertension and the prophylaxis and therapy of thromboembolistic diseases which method comprises administering to said mammal an effective amount of a pharmaceutical composition containing a compound of formula I.
  • lower alkyl may refer to a one to four carbon atom straight or branched hydrocarbon.
  • alkylene of one to four carbon atoms refers to a straight or branched hydrocarbon bonded at each end to other groups and is, for example, ethylene, 1-methylethylene, propylene, butylene, 1-methylpropylene, 2-methylpropylene, or 1,2-dimethylethylene.
  • alkenylene of two to four carbon atoms refers to a straight or branched hydrocarbon chain containing a double bond and bonded to other groups at each end and is, for example, ethylene, allylene, 1-methylethylene, 3-methyl-1-propenylene, 1-butenylene, 2-butenylene, 2-methyl-1-propenylene, and the like.
  • the unsaturation may lie in a branch of the radical, in the straight chain directly between the phenylene radical and the pyridaziriyl radical, or in both positions.
  • the compounds of formula I are useful both in the free base form and in the form of acid addition salts. Both forms are within the scope of the invention.
  • the acid addition salts are a more convenient form for use; and in practice, use of the salt form amounts to use of the base form. In practicing the invention, it was found convenient to form the sulfate, phosphate, or methanesulfonate salts.
  • salts within the scope of the invention are those derived from mineral acids such as hydrochloric acid and sulfamic acid; and organic acids such as ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and the like, giving the hydrochloride, sulfamate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and the like, respectively.
  • the acid addition salts of said basic compounds are prepared either by dissolving the free base in aqueous or aqueous alcohol solution or other suitable solvents containing the appropriate acid and isolating the salt by evaporating the solution, or by reacting the free base and acid in an organic solvent, in which case the salt separates directly or can be obtained by concentration of the solution.
  • the compound of formula I where R 4 is hydrogen nd signifies a double bond may exist in tautomeric forms, that is, as 6-[2-[4-(1H-imidazol-1-yl)phenyl]alkylenyl or alkylene-3(2H)-pyridazinones of formula II or as 6-[2-[4-(1H imidazol-1-yl)phenyl]alkylenyl or alkylene-3-pyridazinols of formula IIA as follows:
  • a preferred embodiment of the present invention is a compound of the formula I, wherein - represents a single or double bond; R 1 , R 2 , R 3 , R 4 , and R 5 are each independently hydrogen or methyl, and A is alkenylene of two to four carbon atoms, or alkylene of one to four carbon atoms, or a pharmaceutically acceptable acid addition salt thereof.
  • Another preferred embodiment is a compound of formula I, wherein is a single or double bond; R 1 , R 2 , R 3 , R 4 , and R 5 are each independently hydrogen or methyl, and A is methylene, ethylene, propylene, or particularly, vinylene.
  • a particular embodiment of the present invention is 4,5-dihydro-6-[2-[4-(1H imidazol-1-yl)phenyl]ethenyl-3(2H)-pyridazinone.
  • the compounds of formula I may be prepared by a process which comprises reacting a y-oxobutanoic acid of the formula wherein A, R 1 , R 2 , R 3 , and R 5 have been defined above, with a R 4 -hydrazine or hydrate thereof, in which R 4 is defined above, in an alcohol solvent or acid/alcohol mixture, such as ethanol or ethanol/acetic acid, at elevated temperatures, such as from 50-100°C, to produce a compound of the formula which, when desired, is converted to a compound of the formula with an oxidizing agent such as manganese dioxide or m-nitrobenzenesulfonic acid according to a procedure described by W. V. Curran and A. Ross in J. Med. Chem., 17, 273 (19
  • y-oxobutanoic acids used as starting materials are known or, if new, may be prepared by known means, for example by condensing the appropriate 4-(1H-imidazol-1-yl)phenylcarboxaldehyde with an oxo-butanoic acid as described in European Patent Applications 81,906 and 85,227.
  • the following schematic diagram illustrates by way of example the preparation of a compound of formula I, wherein A is ethenylene and/or ethylene.
  • the ethylene compound may be obtained by catalytic hydrogenation of the vinylene compound. Palladium on carbon (10%) is preferably used in an alcohol solvent such as ethanol.
  • the usefulness of the compounds of the present invention as cardiotonic agents is demonstrated by their effectiveness in standard pharmacological test procedures, for example, in causing a significant increase in the myocardial contractility in the pentobarbital-anesthetized dog with low or minimal changes in heart rate and blood pressure. This test procedure is described in the following paragraphs.
  • This screen consists of determining the effects of increasing intravenous doses of compound on myocardial contractility (dP/dt max of left ventricular blood pressure), heart rate, and aortic blood pressure of the pentobarbital-anesthetized dog.
  • Left ventricular and aortic blood pressures are recorded on a strip chart recorder.
  • Heart rate using a biotachometer triggered from the R wave of the ECG, and the first derivative of left ventricular blood pressure (dP/dt), obtained with a differentiator amplifier coupled to the corresponding pressure amplifier, are also recorded.
  • a period of at least 30 minutes is utilized to obtain control data prior to administration of test compound.
  • the compounds are dissolved in 0.9% saline solution or in dilute HCI or NaOH (0. or 1.0 N) and are diluted to volume with normal saline. Ethanol or dimethylacetamide can be used as solvents if adequate dilutions can be made. Appropriate vehicle controls are administered when needed.
  • Each dose of the test compound is administered in a volume of 0.1 ml/kg over a period of one minute.
  • the compounds of the present invention when administered intravenously at a rate of about 0.01 to 0.31 mg/kg/min caused dose related significant increases in cardiac contractility with only low or minimal changes in heart rate and moderate reduction in blood pressure.
  • the compounds of the present invention are also useful as antihypertensive agents.
  • the present invention also includes a pharmaceutical composition for increasing cardiac contractility and/or treating hypertension comprising an effective amount of a compound of the formula I as defined above together with a pharmaceutically acceptable carrier.
  • the present invention further includes a method for increasing cardiac contractility and/or treating hypertension in mammals suffering therefrom comprising administering to such mammals either orally or parenterally a corresponding pharmaceutical composition containing a compound of the formula I as defined above in appropriate unit dosage form.
  • the usefulness of the compounds of the present invention as antithrombotic agents is demonstrated by their effectiveness in inhibiting human platelet aggregation in standard in vitro platelet aggregation tests using human platelet-rich plasma.
  • Blood is collected from volunteers who have not injested aspirin or other nonsteroidal antiinflammatory drugs within the preceding two weeks and have not eaten within nine hours before blood draw. Blood is collected in 4.5 ml portions in Vacutainer Number 6462S silicone-coated tubes containing 0.5 ml of 3.8% trisodium citrate. Usually six portions of 4.5 ml are drawn from each volunteer. The blood collected from three or four volunteers is pooled prior to centrifugation. The pooled blood is put in 50 ml polyethylene tubes and centrifuged at 80 xg (ca 600 rpm) in an International Model K centrifuge with number 240 rotor for 20 minutes at room temperature.
  • the platelet content of the PRP is determined with a Coulter Thrombocounter.
  • the PRP is adjusted to a count of 250,000 platelets per microliter using the PPP.
  • Test drugs are dissolved in small amounts of dimethyl sulfoxide (DMSO) followed by dilution with saline (final concentration of DMSO is 1 %). Other lower concentrations are prepared by serial dilution in saline.
  • DMSO dimethyl sulfoxide
  • Platelet-rich plasma adjusted to 250,000 platelets per microliter is distributed in 0.36 ml aliquots into silicone-coated cuvettes of 0.312 inch diameter. Addition of drug solution or saline (0.02 ml) is followed by addition of aggregating agents (ADP or collagen suspension, 0.02 ml). Extent of aggregation (ADP stimulus) or rate of aggregation (collagen stimulus) is determined using the Payton Scientific Dual Channel Aggregation Module, Model 300B. Appropriate concentrations of aggregating agents are determined by an initial brief titration.
  • the major slopes (i.e., the slope of the longest straight line portion) of collagen-induced aggregation curves are determined and compared to the slopes obtained for control aggregation curves (saline and aggregating agent only added). Values obtained are expressed as "percent of control" values. These values are plotted versus drug concentration on semilog paper. Estimates of IC 50 values are made from the resulting curves.
  • 4,5-dihydro-6-[2-[4-(1H imidazol-1-yl)phenyljethenyl]-5-methyl-3-(2H)-piperidazinone had a very potent IC 50 of 7 x 10" M against collagen-induced aggregation and had an IC 50 of 1 x 10 7 M against ADP-stimulated aggregation.
  • the compounds of the present invention may be employed in a method for treating thrombosis in mammals suffering therefrom comprising administering to such mammals, either orally or parenterally, a corresponding pharmaceutical composition containing a compound of the formula I as defined above in "Appropriate Unit Dosage Form".
  • inert, pharmaceutically acceptable carriers can be either solid or liquid.
  • Solid form preparations include powders, tablets, dispersible granules, capsules, cachets, and suppositories.
  • a solid carrier can be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders or tablet disintegrating agents; it can also be encapsulating material.
  • the carrier is a finely divided solid which is in admixture with the finely divided active compound.
  • the active compound is mixed with carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
  • the powders and tablets preferably contain from 5 or 10 to about 70 percent of the active ingredient.
  • Suitable solid carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like.
  • the term "preparation" is intended to include the formulation of the active compound with encapsulating material as carrier providing a capsule in which the active component (with or without other carriers) is surrounded by carrier, which is thus in association with it.
  • cachets are included. Tablets, powders, cachets, and capsules can be used as solid dosage forms suitable for oral administration.
  • a low melting wax such as a mixture of fatty acid glycerides or cocoa butter is first melted, and the active ingredient is dispersed homogeneously therein as by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool and thereby to solidify.
  • Liquid form preparations include solutions, suspensions, and emulsions. As an example may be mentioned water or water propylene glycol solutions for parenteral injection. Liquid preparations can also be formulated in solution in aqueous polyethylene glycol solution.
  • Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizing and thickening agents as desired.
  • Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, i.e., natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents.
  • solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration.
  • liquid forms include solutions, suspensions, and emulsions.
  • These particular solid form preparations are most conveniently provided in unit dose form and as such are used to provide a single liquid dosage unit. Alternately, sufficient solid may be provided so that after conversion to liquid form, multiple individual liquid doses may be obtained by measuring predetemrined volumes of the liquid form preparation as with a syringe, teaspoon, or other volumetric container. When multiple liquid doses are so prepared, it is preferred to maintain the unused portion of said liquid doses at low temperature (i.e., under refrigeration) in order to retard possible decomposition.
  • the solid form preparations intended to be converted to liquid form may contain, in addition to the active material, flavorants, colorants, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.
  • the liquid utilized for preparing the liquid form preparation may be water, isotonic water, ethanol, glycerine, propylene glycol, and the like as well as mixtures thereof. Naturally, the liquid utilized will be chosen with regard to the route of administration, for example, liquid preparations containing large amounts of ethanol are not suitable for parenteral use.
  • the pharmaceutical preparation is in unit dosage form.
  • the preparation is subdivided into unit doses containing appropriate quantities of the active component.
  • the unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, for example, packeted tablets, capsules, and powders in vials or ampoules.
  • the unit dosage form can also be a capsule, cachet, or tablet itself or it can be the appropriate number of any of these in packaged form.
  • the quantity of active compound in a unit dose of preparation may be varied or adjusted from 1 mg to 500 mg preferably to 5 to 10 mg according to the particular application and the potency of the active ingredient.
  • the compositions can, if desired, also contain other compatible therapeutic agents.
  • the mammalian dosage range for a 70 kg subject is from 0.03 to 100 mg/kg of body weight per day or preferably 0.1 to 50 mg/kg of body weight per day.
  • the dosages may be varied depending upon the requirements of the patient, the severity of the condition being treated, and the compound being employed. Determination of the proper dosage for a particular situation is within the skill of the art. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter the dosage is increased by small increments until the optimum effect under the circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day if desired.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Claims (10)

1. Verbindung der folgenden allgemeinen Formel (I)
Figure imgb0022
oder ein pharmazeutisch akzeptables Säureadditionssalz, davon, worin
eine Einfachbindung oder eine Doppelbindung darstellt;
R1, R2 und R3 jeweils unabhängig voneinander ein Wasserstoffatom, ein Niedrig-Cl-C4-Radikal, ein Hydroxy-Niedrig-Cl-C4-Alkylradikal sind, oder R2 und R3, wenn sie zusammengenommen werden und mit den Kohlenstoffatomen, an welche sie gebunden sind, einen 5 bis 7 Kohlenstoffatome enthaltenden Ring oder einen Benzolring bilden;
R4 und R5 jeweils unabhängig voneinander ein Wasserstoffatom oder ein Niedrig-C1-C4-Alkyl repräsentieren; und
A ein Alkylen mit 1 bis 4 Kohlenstoffatomen oder ein Alkenylen mit 2 bis 4 Kohlenstoffatomen ist.
2. Verbindung nach Anspruch 1, worin R1, R2, R3, R4 und Rs jeweils unabhängig voneinander ein Wasserstoffatom oder ein Methylradikal sind.
3. Verbindung nach Anspruch 1 oder 2, worin A ein Vinylen ist.
4. Verbindung nach Anspruch 1, 2 oder 3, welche 4,5-Dihydro-6-[2-[4-(1H-imidazol-1-yl)-phenyl]-ethenyl]-3-(2H)-pyridazinon ist.
5. Verbindung nach Anspruch 1, welche 4,5-Dihydro-6-[2-[4-(4,5,6,7-tetrahydro-1H-benzimidazol-1-yl)-phenyl]-ethenyl]-3(2H)-pyridazinon ist.
6. Verbindung wie im Anspruch 3 beansprucht, welche 4,5-Dihydro-6-[2-[4-(1H-imidazol-1-yl)-phenyl]-ethenyl]-5-methyl-3-(2H)-pyridazinon ist.
7. Verbindung wie im Anspruch 1 beansprucht, welche 4,5-Dihydro-6-[2-[4-(1H-imidazol-1-yl)-phenyl]-ethyl]-3(2H)-pyridazinon ist.
8. Pharmazeutische Zusammensetzung, welche eine wie in irgendeinem vorhergehenden Anspruch beanspruchte Verbindung zusammen mit einem pharmazeutisch akzeptablen Träger oder Verdünnungsmittel umfaßt.
9. Verfahren zur Herstellung einer wie in irgendeinem vorhergehenden Anspruch beanspruchten Verbindung, welches umfaßt: Umsetzung einer Verbindung der Formel:
Figure imgb0023
mit einem R4-Hydrazin oder Hydrat davon, worin R1, R2, R3, R4, R5 und A wie im Anspruch 1 definiert sind, in einem Alkohol oder in Alkohol/Säuremedien bei erhöhter Temperatur und gewünschtenfalls Überführen der resultierenden Verbindung der Formel wie im Anspruch 1 definiert, worin eine Einfachbindung darstellt, in eine entsprechende Verbindung, worin eine Doppelbindung darstellt, mit einem Oxidationsmittel und gewünschtenfalls Überführen einer resultierenden freien Base einer Verbindung der Formel I in ein entsprechendes pharmazeutisch akzeptables Säureadditionssalz.
10. Verbindung der Formel
Figure imgb0024
worin R1, R2, R3, R4 und R5 unabhängig voneinander ein Wasserstoffatom oder ein Methylradikal sind.
EP84308465A 1983-12-07 1984-12-06 6-(2-(4-(1H-Imidazol-1-yl)phenyl-alkylene oder alkenylene-3(2H)-Pyridazinone oder 4,5-Dihydropyridazinone und Verfahren zu deren Herstellung Expired EP0145450B1 (de)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AT84308465T ATE46336T1 (de) 1983-12-07 1984-12-06 6-(2-(4-(1h-imidazol-1-yl)phenyl-alkylene oder alkenylene-3(2h)-pyridazinone oder 4,5dihydropyridazinone und verfahren zu deren herstellung.

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US55916183A 1983-12-07 1983-12-07
US06/669,323 US4599332A (en) 1983-12-07 1984-11-09 4,5-dihydro-6-[2-[4-(1H-imidazol-1-yl)phenyl]-ethenyl]-3(2H)-pyridazinones and related compounds
US559161 2000-04-26
US669323 2000-09-25

Publications (3)

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EP0145450A2 EP0145450A2 (de) 1985-06-19
EP0145450A3 EP0145450A3 (en) 1986-11-26
EP0145450B1 true EP0145450B1 (de) 1989-09-13

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US (1) US4599332A (de)
EP (1) EP0145450B1 (de)
KR (1) KR880002531B1 (de)
AU (1) AU562172B2 (de)
CA (1) CA1244828A (de)
DE (1) DE3479729D1 (de)
DK (1) DK578484A (de)
ES (1) ES8602772A1 (de)
FI (1) FI75819C (de)
GR (1) GR81189B (de)
HU (1) HU193065B (de)
IL (1) IL73628A (de)
NO (1) NO162720C (de)
NZ (1) NZ210458A (de)
PH (1) PH20975A (de)
PT (1) PT79627B (de)

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JPS61158969A (ja) * 1984-12-24 1986-07-18 ワーナー‐ランバート・コンパニー ４，５‐ジヒドロ‐４，４‐ジアルキル‐６‐（置換）フエニル‐３（２ｈ）‐ピリダジノン類
DE3505609A1 (de) * 1985-02-19 1986-08-21 Merck Patent Gmbh, 6100 Darmstadt Benzimidazolyl-pyridazinone
IL79280A (en) * 1985-07-05 1990-07-12 Smith Kline French Lab 4-(6-oxo-dihydro or tetrahydropyridazin-3-yl)benzene derivatives,their preparation and pharmaceutical compositions containing them
US4783463A (en) * 1985-10-23 1988-11-08 Rorer Pharmaceutical Corporation Pyridyl-pyridazinone and pyridyl-pyrazolinone compounds and their use in the treatment of congestive heart failure
US4826835A (en) * 1985-10-23 1989-05-02 Rorer Pharmaceutical Corporation Pyridyl-pyridazinone and pyridyl-pyrazolinone compounds and their use in the treatment of congestive heart failure
US5185332A (en) * 1989-02-11 1993-02-09 Orion-Yhtyma Oy Thiadiazines and pharmaceutical compositions thereof as well as method of use
GB8903130D0 (en) * 1989-02-11 1989-03-30 Orion Yhtymae Oy Substituted pyridazinones
CA2205757C (en) * 1996-05-30 2006-01-24 F. Hoffmann-La Roche Ag Pyridazinone derivatives and their use as inhibitors of prostaglandin g/h synthase i and ii(cox i and ii)

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DE3130251A1 (de) * 1981-07-31 1983-02-17 A. Nattermann & Cie GmbH, 5000 Köln 6-(4-((omega)-(1-imidazolyl)-alkyl)-phenyl)-3-oxo -2,3,4,5-tetrahydro-pyridazine und deren saeureadditionssalze, verfahren zu ihrer herstellung und diese enthaltende pharmazeutische praeparate
DE3130252A1 (de) * 1981-07-31 1983-02-17 A. Nattermann & Cie GmbH, 5000 Köln 6-(5-((omega)-(1-imidazolyl)-alkyl)-thien-2-yl)-3-oxo-2,3,4,5-tetrahydro-pyridazine und deren saeureadditionssalze, verfahren zu ihrer herstellung und diese enthaltende pharmazeutische praeparate
US4353905A (en) * 1981-09-17 1982-10-12 Warner-Lambert Company Substituted 4,5-dihydro-6-[4-(1H-imidazol-1-yl)phenyl]-3(2H)-pyridazinones and 6-[4-(1H-imidazol-1-yl)phenyl]-3(2H)-pyridazinones
HU190412B (en) * 1981-09-17 1986-09-29 Warner-Lambert Co,Us Process for producing substituted 4,5-dihiydro-6-bracket-substituted-bracket closed-phenyl-3-bracket-2h-bracket closed-pyridazinones and 6-bracket-substituted-bracket closed-phenyl-3-bracket-2h-bracket closed-pyridazinones
CA1199027A (en) * 1981-11-12 1986-01-07 Stuart D. Mills Heterocyclic derivatives of pyridazinone, thiadiazinone, oxadiazinone and triazinone
DE3212304A1 (de) * 1982-04-02 1983-10-06 Nattermann A & Cie Imidazolylphenyl-tetrahydropyridazine, verfahren zu ihrer herstellung und diese enthaltende pharmazeutische praeparate
US4508718A (en) * 1984-01-16 1985-04-02 Warner-Lambert Company Cardiotonic and antihypertensive oxadiazinone compounds
DE3401911A1 (de) * 1984-01-20 1985-08-01 A. Nattermann & Cie GmbH, 5000 Köln Substituierte 4,5-dihydro-6-vinyl-3(2h)-pyridazinone und 6-vinyl-3(2h)-pyridazinone sowie verfahren zu ihrer herstellung

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KR850004481A (ko) 1985-07-15
FI75819B (fi) 1988-04-29
KR880002531B1 (ko) 1988-11-28
PT79627A (en) 1985-01-01
AU3635584A (en) 1985-06-13
ES538242A0 (es) 1985-12-01
AU562172B2 (en) 1987-05-28
GR81189B (en) 1985-04-08
EP0145450A2 (de) 1985-06-19
NO162720C (no) 1990-02-07
ES8602772A1 (es) 1985-12-01
PH20975A (en) 1987-06-15
DK578484A (da) 1985-06-08
HU193065B (en) 1987-08-28
US4599332A (en) 1986-07-08
FI844822L (fi) 1985-06-08
FI75819C (fi) 1988-08-08
CA1244828A (en) 1988-11-15
NO162720B (no) 1989-10-30
FI844822A0 (fi) 1984-12-05
NO844883L (no) 1985-06-10
DE3479729D1 (en) 1989-10-19
DK578484D0 (da) 1984-12-05
EP0145450A3 (en) 1986-11-26
IL73628A (en) 1987-10-20
HUT36473A (en) 1985-09-30
IL73628A0 (en) 1985-02-28
NZ210458A (en) 1987-06-30
PT79627B (en) 1986-12-12

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